1. Molecular Dynamics Simulations Reveal the Mechanisms of Allosteric Activation of Hsp90 by Designed Ligands
- Author
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Anna Bernardi, Jiahui Tao, Sara Sattin, Giorgio Colombo, Elisabetta Moroni, Gerolamo Vettoretti, and David A. Agard
- Subjects
Models, Molecular ,0301 basic medicine ,Saccharomyces cerevisiae Proteins ,Protein Conformation ,1.1 Normal biological development and functioning ,Allosteric regulation ,Chemical ,Molecular Dynamics Simulation ,Ligands ,010402 general chemistry ,01 natural sciences ,Molecular Docking Simulation ,Article ,03 medical and health sciences ,Molecular dynamics ,Protein structure ,Allosteric Regulation ,Underpinning research ,Models ,Protein Interaction Domains and Motifs ,HSP90 Heat-Shock Proteins ,Adenosine Triphosphatases ,Multidisciplinary ,biology ,Chemistry ,Molecular ,Hsp90 ,0104 chemical sciences ,Kinetics ,030104 developmental biology ,Models, Chemical ,Allosteric enzyme ,Chaperone (protein) ,biology.protein ,Biophysics ,Generic health relevance ,Target protein ,SHOCK-PROTEIN 90 ,HEAT-SHOCK-PROTEIN-70 HSP70 INHIBITOR ,ATP HYDROLYSIS ,CONFORMATIONAL DYNAMICS ,SUBSTRATE RECOGNITION ,ESCHERICHIA-COLI ,DRUG DISCOVERY ,CHAPERONE ,ENZYMES ,PRINCIPLES ,Molecular Chaperones ,Protein Binding - Abstract
Controlling biochemical pathways through chemically designed modulators may provide novel opportunities to develop therapeutic drugs and chemical tools. The underlying challenge is to design new molecular entities able to act as allosteric chemical switches that selectively turn on/off functions by modulating the conformational dynamics of their target protein. We examine the origins of the stimulation of ATPase and closure kinetics in the molecular chaperone Hsp90 by allosteric modulators through atomistic molecular dynamics (MD) simulations and analysis of protein-ligand interactions. In particular, we focus on the cross-talk between allosteric ligands and protein conformations and its effect on the dynamic properties of the chaperone’s active state. We examine the impact of different allosteric modulators on the stability, structural and internal dynamics properties of Hsp90 closed state. A critical aspect of this study is the development of a quantitative model that correlates Hsp90 activation to the presence of a certain compound, making use of information on the dynamic adaptation of protein conformations to the presence of the ligand, which allows to capture conformational states relevant in the activation process. We discuss the implications of considering the conformational dialogue between allosteric ligands and protein conformations for the design of new functional modulators.
- Published
- 2016
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